Phytochemistry and Biological Activities of Murraya Species

Murraya is a plant genus within the Rutaceae family comprising over 17 species, which are widely distributed in Asia, Australia, and the Pacific Islands. Furthermore, these species have been used in traditional medicine to treat fever, pain, and dysentery. Several reports have also extensively studied the leaves, seeds, stembark, and bark of Murraya from 1965 to 2023 to explore their natural product composition. Various phytochemical studies have revealed the isolation of 413 compounds recorded, comprising coumarins, terpenoids, flavonoids, and aromatics, as well as alkaloids, which constitute the largest proportion (46.9%). These isolated compounds have long been known to exhibit different bioactivities, such as cytotoxic and anti-inflammatory properties. Cytotoxic activity has been observed against HCT 116, HeLa, HepG2, and other cell lines. Previous studies have also reported the presence of antifungal, hepatoprotective, antihyperlipidemic, antidiarrheal, and antioxidant effects. Therefore, this review provides a comprehensive overview of Murraya species, highlighting their phytochemistry, biological activities, and potential as a source of active natural compounds.


Introduction
The Rutaceae family comprises over 150 genera that are distributed across the globe. Furthermore, one of these genera is Murraya, consisting of 17 species, which are spread across Asia, Australia, and the Pacific region. The ethnobotanical applications of the genus encompass a diverse range of uses, such as the landscaping of construction buildings, and some species can be grafted onto citrus rootstocks. Various plant parts of its members have also been used in traditional medicine to treat fever, pain, and dysentery [1].
The rapid growth of health problems has necessitated the need for urgent solutions, thereby making bioactive compounds from Murraya a starting point for drug development.
Over the course of 56 years, extensive studies have been conducted on the Marraya genus, leading to the identification of five classes of metabolites, with alkaloids being the main component. Based on the findings, there are no extensive reports on the phytochemistry and biological activities of the entire genus. Therefore, this review provides a main component. Based on the findings, there are no extensive reports on the phytochemistry and biological activities of the entire genus. Therefore, this review provides a comprehensive overview of Murraya species, highlighting their phytochemistry, biological activities, and potential as a source of active natural compounds. The results of this study are expected to serve as a foundation for future studies, which aim to identify chemical content from natural resources and discover new drugs.

Methodology
This study started with a literature search on Murraya species and all the synonyms were confirmed from the plant list (theplantlist.org, [accessed 20 Februari 2023]), International Plant Names Index (ipni.org, [accesssed 20 Februari 2023]), Royal Botanical Gardens (kew.org), [accessed 20 Februari 2023]), and tropicos (tropicos.org, [accessed 20 Februari 2023]) databases. Furthermore, literature articles were collected from databases such as SciFinder, PubMed, Google Scholar, and Scopus. These articles were filtered based on their abstracts or keywords. A collection of relevant papers published between 1963 and 2023 was then obtained, focusing on the biological and phytochemical properties of Marraya. A systematic review was carried out using a flow diagram and meta-analysis studies were gathered from the database search. The identification of relevant papers was carried out with an approach involving title screening, gray literature exploration, review, excluding primary sources, and the removal of duplicate entries. The selected papers were then collected and subjected to further analysis, as shown in Figure 1 [9].

Botany
The plants in the genus Murraya were often angiosperms widely distributed in tropical and subtropical regions, including East, Southern, and Southeast Asia, northern Australia, and several areas in South America. The plants were characterized by an average maximum height of 3.5 m, with alternate and odd-pinnate leaves, as well as terminal and/or axillary inflorescence. The seeds typically had a seed coat that could be membranous or fleshy, with straight embryos and elliptic cotyledons. Furthermore, the hypocotyl was partially enclosed between the cotyledons, with four or five petals [1]. One of the Murraya species, Murraya paniculata, is known as orange jasmine or kemuning in Indonesia and some other countries [10]. Additionally, the species Murraya koenigii is widely

Botany
The plants in the genus Murraya were often angiosperms widely distributed in tropical and subtropical regions, including East, Southern, and Southeast Asia, northern Australia, and several areas in South America. The plants were characterized by an average maximum height of 3.5 m, with alternate and odd-pinnate leaves, as well as terminal and/or axillary inflorescence. The seeds typically had a seed coat that could be membranous or fleshy, with straight embryos and elliptic cotyledons. Furthermore, the hypocotyl was partially enclosed between the cotyledons, with four or five petals [1]. One of the Murraya species, Murraya paniculata, is known as orange jasmine or kemuning in Indonesia and some other countries [10]. Additionally, the species Murraya koenigii is widely known as curry tree and the leaves are commonly used as a part of local cuisine in India [11][12][13] (Figure 2). The edibility of this variety of Murraya plants has been studied. Liaqat et al. [14], in the research on the toxicology of the Rutaceae family, including Murraya, stated that the oil content from Murraya is considered safe for internal use with caution.
Molecules 2023, 28, x FOR PEER REVIEW 3 o known as curry tree and the leaves are commonly used as a part of local cuisine in In [11][12][13]. The edibility of this variety of Murraya plants has been studied. Liaqat et al. [ in the research on the toxicology of the Rutaceae family, including Murraya, stated t the oil content from Murraya is considered safe for internal use with caution.

Overview of Isolated Compounds from Murraya Species
A total of 413 compounds were isolated based on the data obtained from the lite ture published between 1965 and 2023. The compounds isolated from the stem bark, ba roots, leaves, and twigs of Murraya species included alkaloids, coumarin, flavonoids, s oids, terpenoids, and other components. Furthermore, previous reports suggested t alkaloids were the dominant metabolites, with a total of 193 compounds (46.9%), follow by coumarin and flavonoid with 121 (29.3%) and 48 (10.3%), respectively ( Figure 3).

Overview of Isolated Compounds from Murraya Species
A total of 413 compounds were isolated based on the data obtained from the literature published between 1965 and 2023. The compounds isolated from the stem bark, bark, roots, leaves, and twigs of Murraya species included alkaloids, coumarin, flavonoids, steroids, terpenoids, and other components. Furthermore, previous reports suggested that alkaloids were the dominant metabolites, with a total of 193 compounds (46.9%), followed by coumarin and flavonoid with 121 (29.3%) and 48 (10.3%), respectively ( Figure 3). [11][12][13]. The edibility of this variety of Murraya plants has been studied. Liaqat e in the research on the toxicology of the Rutaceae family, including Murraya, sta the oil content from Murraya is considered safe for internal use with caution.

Overview of Isolated Compounds from Murraya Species
A total of 413 compounds were isolated based on the data obtained from th ture published between 1965 and 2023. The compounds isolated from the stem ba roots, leaves, and twigs of Murraya species included alkaloids, coumarin, flavono oids, terpenoids, and other components. Furthermore, previous reports sugges alkaloids were the dominant metabolites, with a total of 193 compounds (46.9%), by coumarin and flavonoid with 121 (29.3%) and 48 (10.3%), respectively (Figure

Biological Activities
Murraya plant parts have long been used in several regions as traditional medicines to treat dysentery, fever, and dizziness. Several studies have also shown that the extracts and compounds obtained from the genus exhibited various bioactivities, including cyto-

Biological Activities
Murraya plant parts have long been used in several regions as traditional medicines to treat dysentery, fever, and dizziness. Several studies have also shown that the extracts and compounds obtained from the genus exhibited various bioactivities, including cytotoxicity, anti-inflammatory, antidiarrheal, antihyperlipidemic, and antioxidant properties ( Table 5). The active compounds have potential for medicine purposes.

Cytotoxicity Properties
Ma et al. [2] reported that mahanine (26) showed significant cytotoxicity against four cell lines and PCK2 protein, with SPR (surface plasmon resonance) being identified as the possible mechanism. Furthermore, the potential binding sites were disclosed as Phe 525, Arg 436, Phe 530, Asn 533, and Gly 289. Changes in nuclear morphology, DNA breakage, activation-like activities, cleavage of poly(ADP-ribose) polymerase, release of cytochrome C into the cytoplasm, and stimulation of reactive oxygen species formation were observed to be signs of mahanine-induced cell death. Mahanine triggered the caspase-3, 6, 8, and 9 activities, but did not affect caspase-1-like activity [85]. Koenimbine (58) from M. koenigii showed the most potent inhibitory activity against B16 melanoma 4A5. Similar activity was also reported in Mahanimbine (64) and 2 other compounds (17 and 52) [31].
A previous study stated that three compounds from M. Koenigii, including pyrayafoline D, induced apoptotic cell death in HL-60 cell lines at a concentration of 30 µM. The apoptotic effect of these compounds was observed to be mediated by the loss of mitochondrial membrane potential and the subsequent activation of caspase-9/caspase-3 [32]. Furthermore, CHCl 3 extract and koenoline (80) from M. koenigii exhibited cytotoxic activity with an ED 50 range of 4.0 µg/mL to 26 µg/mL [38].
The primary screening results showed that compounds derived from M. siamensis had inhibitory activity. All test coumarins obtained through isolation showed a potent dose-dependent inhibitory effect on EBV-EA induction via TPA. Murrayacoumarin A (304) bearing an oxygenated geranyloxy side chain exhibited the most potent activity [74].

Anti-Inflammatory Properties
Studies on the biological activities of plants from the Murraya genus identified the presence of anti-inflammatory activity. Furthermore, Murrayanine (98) from M. kwangsiensis showed significant inhibition of NO production in lipopolysaccharide-stimulated BV-2 microglial cells compared to a positive control [3]. Another study reported that three compounds from M. paniculata, including Panitin D (283), exotimarin I (287), and transdehydroosthol (290), showed moderate inhibitory effects on LPS-induced NO production in BV-2 microglial cells [57].

Antidiarrheal Properties
Mandal et al. [5] reported that kurryam (57) and koenimbine (58) exhibited significant inhibitory activity against castor-oil-induced diarrhea and PGE 2 -induced enteropooling in rats. Furthermore, a dose of 30 mg/kg had an equivalent effect to 5 mg/kg of the standard drug.

Conclusions
In conclusion, Murraya species have been extensively studied, thereby contributing to the understanding of secondary metabolites and their biological activities in nature. Furthermore, alkaloids were observed to be the dominant compounds from Murraya, followed by coumarins and flavonoids. The literature reports showed that the genus exhibited various biological activities, such as cytotoxic and anti-inflammatory effects.  Data Availability Statement: The study did not report any data.